Maternal Exposure to Dibutyl Phthalate (DBP) or Diethylstilbestrol (DES) Leads to Long-Term Changes in Hypothalamic Gene Expression and Sexual Behavior

Abstract

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8–12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior.

Expression and Role of INSL3 in the Fetal Testis

“…The chief mode of action of these substances appears to be to disrupt fetal Leydig cell differentiation leading to a reduction in testosterone production and/or INSL3. Importantly, even after only a brief maternal exposure, these substances also appear to affect Leydig stem cells which reside within the testes even into adulthood, and hence may also influence puberty and adult Leydig cell function ( 67 , 69 ).…”

Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

“…Given the estrogen-mediated regulation of female behavior and neuroendocrine responses, indications were made in the tables with respect to the identification or not of the stage of the estrous cycle in adult females. [51][52][53] or DINP [53] on the expression of female sexual behavior in rats (Table 1). One study reported a lower lordosis quotient at all tested doses [53] while the two other studies found no effect [51,52].…”

“…Developmental exposure. Three studies addressed the effects of developmental exposure to high doses of DBP [ 51 , 52 , 53 ] or DINP [ 53 ] on the expression of female sexual behavior in rats ( Table 1 ). One study reported a lower lordosis quotient at all tested doses [ 53 ] while the two other studies found no effect [ 51 , 52 ].…”

“…Three studies addressed the effects of developmental exposure to high doses of DBP [ 51 , 52 , 53 ] or DINP [ 53 ] on the expression of female sexual behavior in rats ( Table 1 ). One study reported a lower lordosis quotient at all tested doses [ 53 ] while the two other studies found no effect [ 51 , 52 ]. These three studies had not only the use of very high phthalate doses in common but also the assessment of lordosis behavior in intact females at the proestrus or estrus stage.…”

Integrated Genomic and Bioinformatics Approaches to Identify Molecular Links between Endocrine Disruptors and Adverse Outcomes

“…DES fetal exposure causes other toxic effects in women, in addition to adversely affecting male reproduction [ 72 , 86 ]. DES perturbs global gene expression across different tissues in males and females [ 72 , 87 , 88 , 89 ].…”